Is MYO7A p.Tyr1580Cys (c.4739A>G) pathogenic?

MYO7A p.Tyr1580Cys (c.4739A>G) is classified Uncertain significance in MYO7A (ClinVar, Multiple submitters, 12 submitters; last evaluated 2025-01-06). AlphaMissense: likely pathogenic (0.9428); Ultra-rare (popmax 0.0353%, nfe); Associated with Usher syndrome type 1.

What condition is associated with MYO7A p.Tyr1580Cys (c.4739A>G)?

MYO7A p.Tyr1580Cys (c.4739A>G) is associated with Usher syndrome type 1, hearing loss disorder, autosomal recessive nonsyndromic hearing loss 2 (ClinVar).

How common is MYO7A p.Tyr1580Cys (c.4739A>G) in the general population?

MYO7A p.Tyr1580Cys (c.4739A>G) is ultra-rare (popmax 0.0353%, nfe) (gnomAD).

How is Usher syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about MYO7A p.Tyr1580Cys (c.4739A>G)?

AlphaMissense predicts likely pathogenic (score 0.9428) — an in-silico prediction, not a clinical call.

MYO7A p.Tyr1580Cys

c.4739A>G · rs370232066 · VCV43256

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 12 submitters

AlphaMissense

likely pathogenic

0.9428 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0353%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Usher syndrome type 1

Computational evidence

Protein change
AlphaMissense	0.9428	likely pathogenic
REVEL	0.937	strongly pathogenic-leaning
SaProt	LLR -12.50	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.4, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 84 kb · p 0.0065 · regional, not allelic
Overall
CADD	26.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0353% European (non-Finnish) · 417/1,179,848 alleles

Filtering AF 0.0325% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0314%

Overall 0.0265% 428/1,613,572 alleles · ultra-rare exomes 402/1,461,390 · genomes 26/152,182 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0353%	2,829
African / African-American	0.00801%	12,487
Remaining individualsnot grpmax-eligible	0.0064%	15,615
Finnishnot grpmax-eligible	0.00157%	63,874

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: MYO7A
Protein: p.Tyr1580Cys
Coding: c.4739A>G
MANE Select: NM_000260
dbSNP: rs370232066
Type: single nucleotide variant
Location: chr11:77199705 (GRCh38)
Gene constraint: LOEUF 0.995 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.73 · 1 PDB
Residue 1580: the ferm 1 domain

Full MYO7A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Usher syndrome type 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hearing loss disorder autosomal recessive nonsyndromic hearing loss 2 autosomal dominant nonsyndromic hearing loss 11 inherited retinal dystrophy Usher syndrome type 1B

For Usher syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy, Neonatal
Prevalence: 1-9 / 100 000 (Worldwide)

Similar variants

MYO7A p.Ala1288Pro Likely pathogenic ★★★ same condition
MYO7A p.Arg1168Gln Pathogenic ★★★ ⚠ same condition
MYO7A p.Arg1873Gln Pathogenic ★★★ ⚠ same condition
MYO7A p.Arg395Cys Likely pathogenic ★★★ ⚠ same condition
MYO7A p.Arg668Cys Pathogenic ★★★ same condition
MYO7A p.Arg853His Likely pathogenic ★★★ same condition
MYO7A p.Glu968Asp Likely pathogenic ★★★ ⚠ same condition
MYO7A p.Gly2187Asp Likely pathogenic ★★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/myo7a-p-tyr1580cys (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown